Anti-myelin-associated glycoprotein neuropathy is a demyelinating peripheral neuropathy, caused by autoantibodies recognizing the antigenic HNK-1 carbohydrate epitope, found on myelin-associated glycoprotein (MAG) and other glycoconjugates of the peripheral nervous system (PNS). The clinical picture is characterized by a slowly progressing demyelinating, predominantly sensory neuropathy. The correlation of high levels of antibodies and demyelination is well established. Thus, pathological studies on nerve biopsies from patients show demyelination and widening of myelin lamellae, as well as deposits of anti-MAG IgM on myelin. Furthermore, therapeutic reduction of the IgM antibody concentration leads to clinical improvement of neuropathic symptoms. (A. J. Steck et al., Current Opinion in Neurology 2006, 19:458-463; M. C. Dalakas, Current Treatment Options in Neurology 2010, 12:71-83).
The myelin glycoconjugates that contain the HNK-1 epitope include the glycoproteins MAG, protein zero (P0), peripheral myelin protein-22 (PMP22), as well as the glycolipids sulfoglucuronyl paragloboside (SGPG) and sulfoglucuronyl lactosaminyl paragloboside (SGLPG). Several observations suggest MAG as major target for the IgM antibodies: (i) Deposits of patients' antibodies to PNS sites are co-localized with MAG, (ii) MAG is selectively lost from myelin, and (iii) the human nerve pathology and MAG-knockout mice show characteristic similarities (R. H. Quarles, Journal of Neurochemistry 2007, 100: 1431-1448).
MAG belongs to the family of sialic acid-binding immunoglobulin-like lectins (Siglecs). It is located mainly in periaxonal membranes of oligodendroglial cells in the CNS and Schwann cells in the PNS and is involved in adhesion and signaling processes at the axon-glia interface (R. H. Quarles, 2007, loc. cit.). MAG is strongly glycosylated, i.e. 30% of its molecular weight is contributed by heterogeneous N-linked oligosaccharides. All of the potential eight N-glycosylation sites of MAG can carry the HNK-1 epitope. The two glycolipids (SGPG, SGLPG) carrying the HNK-1 epitope contain 3-O-sulfoglucuronic acid (SO3-3GlcA) as a specific hallmark (T. Ariga et al., J Biol Chem 1987, 262:848-853). Interestingly, the HNK-1 epitope structure of bovine glycoprotein P0 also contains this characteristic feature. The similarity between the three elucidated structures is restricted to the terminal trisaccharide. Consequently the HNK-1 epitope was defined as SO3-3-GlcA(β1-3)Gal(β1-4)GlcNAc—OH.
The precise carbohydrate epitope recognized by IgM antibodies remains unclear. A study with SGPG derivatives showed that the IgM antibodies place different importance on the carboxyl and the sulfate group. Whereas “intact” SGPG, containing both negatively charged groups, was reported as optimal epitope for antibody binding (A. A. Ilyas et al., J Neurochemistry 1990, 55:594-601), other studies emphasize the importance of the length of the carbohydrate chain for antibody recognition. Furthermore, the SO3-3-GlcA(β1-3)Gal disaccharide epitope seems to be the minimum requirement for binding (A. Tokuda et al., J. Carbohydrate Chemistry 1998, 17:535-546).